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United States Patent |
5,248,797
|
Sum
|
September 28, 1993
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Method for the production of 9-amino-6-demethyl-6-deoxytetracycline
Abstract
The invention relates to a novel method for producing [4S-(4alpha,
12aalpha)]-9-amino-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,
10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide, hereinafter
called 9-amino-6-demethyl-6-deoxytetracycline, which compound is a
valuable intermediate for synthesis of tetracyclines.
Inventors:
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Sum; Phaik-Eng (Pomona, NY)
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Assignee:
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American Cyanamid Company (Stamford, CT)
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Appl. No.:
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928587 |
Filed:
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August 13, 1992 |
Current U.S. Class: |
552/205 |
Intern'l Class: |
C07C 235/66 |
Field of Search: |
552/205
|
References Cited
U.S. Patent Documents
Re26253 | Aug., 1967 | Petisi | 260/559.
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Re26271 | Sep., 1967 | Boothe | 260/559.
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3043875 | Jul., 1962 | Beereboom | 260/559.
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3226436 | Dec., 1965 | Petisi | 260/559.
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3338963 | Aug., 1967 | Petisi et al. | 552/205.
|
Other References
Boothe et al, J. Amer. Chem. Soc., vol. 82, pp. 1253-1254 (1960).
Spencer et al, J. Med. Chem., vol. 6, pp. 405-407 (1963).
|
Primary Examiner: Cintins; Marianne M.
Assistant Examiner: Kestler; Kimberly J.
Attorney, Agent or Firm: Szatkowski; Thomas S.
Claims
I claim:
1. A process for producing 9-Amino-6-de-methyl-6-deoxytetracycline mineral
acid salt which comprises:
(a) reacting 6-demethyl-6-deoxytetracycline, in cold concentrated mineral
acid, with a halogenating agent at a temperature from 0.degree. C. to
about 20.degree. C. and recovering
7-halogen-6-demethyl-6-deoxytetracycline mineral acid salt by filtration
or recrystallization; and
(b) reacting the 7-halogen-6-demethyl-6-deoxytetracycline mineral acid
salt, in a cold concentrated mineral acid, with a slight molar excess of a
nitrating reagent at temperature ranges from -15.degree. C to +15.degree.
C. and recovering 7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral
acid salt by filtration or recrystallization; and
(c) reducing, at room temperature, the
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt, in a
solvent, with Group VIII metal catalysts, their salts or rare metal oxides
at between 1 and 40 psi, isolating the product by dilution in an alcohol
and recovering 9-amino-6-demethyl-6-deoxytetracycline mineral acid salt.
2. The process of claim 1 wherein said halogenating agent comprises
bromine, N-chlorosuccinimide, N-bromosuccinimide, iodine monochloride or
benzyltrimethylammonium dichloroiodate.
3. The process of claim 2 wherein said halogenating agent comprises
N-bromosuccinimide.
4. The process of claim 1 wherein said concentrated mineral acid comprises
concentrated sulfuric acid.
5. The process of claim 1 wherein said temperature for step a is maintained
at 0.degree. C.
6. The process of claim 1 wherein said
7-halogen-6-demethyl-6-deoxytetracycline mineral acid salt is recovered by
filtration.
7. The process of claim 1 wherein said
7-halogen-6-demethyl-6-deoxytetracycline mineral acid salt is
recrystallized from a mixture of 2-methoxy-ethanol, methanol and diethyl
ether.
8. The process of claim 1 wherein said nitrating reagent comprises a "mixed
acid" or a metal nitrate salt.
9. The process of claim 8 wherein said "mixed acid" comprises 1.1 to 1.2
equivalents of 10% nitric acid in concentrated sulfuric acid.
10. The process of claim 1 wherein said mineral acid comprises cold
concentrated sulfuric acid.
11. The process of claim 1 wherein said temperature for step b is
maintained at 0.degree. C.
12. The process of claim 1 wherein said
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt is
recovered by filtration.
13. The process of claim 1 wherein said Group VIII metal catalyst, their
salts or rare earth oxides comprises 10-30% by weight of Pt on activated
carbon, Pd on activated carbon, rhodium on activated carbon, ruthenium on
activated carbon or iridium on activated carbon.
14. The process of claim 13 wherein said Group VIII metal catalyst
comprises 10 to 30% by weight of 10% palladium on activated carbon.
15. The process of claim 1 wherein said solvent for step c is a 5:1 mixture
of 2-methoxyethanol:lN sulfuric or hydrochloric acid, methanol:lN sulfuric
or hydrochloric acid or ethanol:lN sulfuric or hydro-chloric acid.
16. The process of claim 15 wherein said solvent comprises a 5:1 mixture of
2-methoxyethanol:lN sulfuric acid.
17. The process of claim 1 wherein said
9-Amino-6-demethyl-6-deoxytetracycline mineral acid salt is isolated by
dilution with isopropanol.
18. The process of claim 1 wherein said
9-Amino-6-demethyl-6-deoxytetracycline mineral acid salt is recovered by
filtration.
19. A process for producing 9-Amino-6-demethyl-6-deoxytetracycline mineral
acid salt which comprises:
(a) reacting 6-demethyl-6-deoxytetracycline, in cold concentrated mineral
acid, with a halogenating agent at a temperature from 0.degree. C. to
about 20.degree. C. followed by the addition of a slight molar excess of a
solid metal nitrate salt or a "mixed acid" at temperature ranges of from
-15.degree. C. to +15.degree. C., diluting with a solvent and recovering
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt; and
(b) reducing, at room temperature, the
7-halogen-9nitro-6-demethyl-6-deoxytetracycline mineral acid salt, in a
solvent, with Group VIII metal catalysts, their salts or rare metal oxides
at between 1 and 40 psi, isolating the product with an alcohol and
recovering 9-amino-6- demethyl-6-deoxytetracycline mineral acid salt.
20. The process of claim 19 wherein said halogenating agent comprises
bromine, N-bromosuccinimide, N-chlorosuccinimide, iodine monochloride or
benzyltrimethylammonium dichloroiodate.
21. The process of claim 20 wherein said halogenating agent is
N-bromosuccinimide.
22. The process of claim 19 wherein said concentrated mineral acid
comprises concentrated sulfuric acid.
23. The process of claim 19 wherein said temperature for step a is
maintained at 0.degree. C.
24. The process of claim 19 wherein said metal nitrate salt comprises a 10%
molar excess of potassium nitrate.
25. The process of claim 19 wherein said "mixed acid" comprises 1.1 to 1.2
equivalents of 10% nitric acid in concentrated sulfuric acid.
26. The process of claim 19 wherein said
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt is
recovered by dilution with diethyl ether.
27. The process of claim 26 wherein said
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt is
purified by trituration with alcohols, dilution of the filtrate with
diethyl ether and filtration to collect the resulting pure
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt.
28. The process of claim 27 wherein said alcohols comprises methyl alcohol
and isopropyl alcohol.
29. The process of claim 19 wherein said Group VIII metal catalyst, their
salts or rare earth oxides comprises 10-30% by weight of Pt on activated
carbon, Pd on activated carbon, rhodium on activated carbon, ruthenium on
activated carbon or iridium on activated carbon.
30. The process of claim 29 wherein said Group VIII metal catalyst
comprises 10 to 30% by weight of 10% palladium on activated carbon.
31. The process of claim 19 wherein said solvent for step c is a 5:1
mixture of 2-methoxyethanol:1N sulfuric or hydrochloric acid, methanol:lN
sulfuric or hydrochloric acid or ethanol:lN sulfuric or hydrochlor acid.
32. The process of claim 31 wherein said solvent comprises a 5:1 mixture of
2-methoxyethanol:lN sulfuric acid.
33. The process of claim 19 wherein said
9-Amino-6-demethyl-6-deoxytetracycline mineral acid salt isolated by
dilution with isopropanol.
34. The process of claim 32 wherein said
9-Amino-6-demethyl-6-deoxytetracycline mineral acid salt is recovered by
filtration.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a novel method for producing [4S-(4alpha,
12aalpha)]-9-amino-4-(dimethylamino)
-1,4,4a,5,5a,6,11,12a--octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-nap
hthacenecarboxamide, hereinafter called
9-amino-6-demethyl-6-deoxytetracycline, which compound is a valuable
intermediate for synthesis of tetracyclines.
2. Description of Prior Art
9-Amino-6-demethyl-6-deoxytetracycline is known and useful as a final
product and as an intermediate for the synthesis of substituted
tetracyclines [U.S. Pat. No. 3,219,671 and 3,226,436; Journal of the
American Chemical Society, 82, 1253(1960)].
Prior to the present invention 9-amino-6-demethyl-6-deoxytetracycline was
made by nitrating 6-demethyl-6-deoxytetracycline, followed by catalytic
reduction to give the desired product (Boothe, J. H. et al., Journal of
the American Chemical Society, 82, 1253 (1960)). This method, however,
produces a 1:1.5 mixture of 7- and 9-nitro-6-demethyl-6-deoxytetracyclines
which are difficult to separate. When conventional techniques of
purification are used, such as crystallization or column chromatography,
9-nitro-6-demethyl-6-deoxotetracycline is obtained in 39% yield. Even
these conventional purification techniques, however, do not provide
9-nitro-6-demethyl-6-deoxytetracycline with 100% purity. Some
7-nitro-6-demethyl-6-deoxytetracycline is still present as a contaminant.
The 9-nitro so obtained is then reduced to
9-amino-6-demethyl-6-deoxytetracycline. However, due to the previously
described difficulty in separating the
7-nitro-6-demethyl-6-deoxytetracycline from the
9-nitro-6-demethyl-6-deoxytetracycline, some
7-amino-6-demethyl-6-deoxytetracycline is also produced.
SUMMARY OF THE INVENTION
It has now been found that 9-amino-6-demethyl-6-deoxytetracycline mineral
acid salt, 4, can be made with exceptional purity and yield by reacting
6-demethyl-6-deoxytetracycline, 1, with a halogenating agent in a
concentrated mineral acid (U.S. Pat. No. 3,036,129) to yield
7-halogen-6-demethyl-6-deoxytetracyline mineral acid salt, 2, with only
minor amounts of the 7,9-dihalogen-6-demethyl-6-deoxytetracycline
contaminant. In any event, the
7,9-dihalogen-6-demethyl-6-deoxytetracycline is easily separated, by
crystallization, from the desired 7-halogen-6-demethyl-6-deoxytetracycline
mineral acid salt,2.
The 7-halogen-6-demethyl-6-deoxytetracycline mineral acid salt, 2, is then
nitrated to give 7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral
acid salt, 3, Because the 7-position is occupied with a halogen, this
nitration provides 7-halogen-9-nitro-6-demethyl-6-deoxytetracycline
mineral acid salt with exceptional purity and yield.
Preferably, the halogenation and nitration are carried out in one step by
reacting 6-demethyl-6-deoxytetracycline, 1, with a halogenating agent in a
concentrated mineral acid, followed by the addition of a nitrating reagent
to afford substantially pure
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt, 3.
The 7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt, 3,
is in turn reduced to give exceptionally pure
9-amino-6-demethyl-6-deoxytetracycline mineral acid salt, 4, in high
yield. This reduction cleaves the halogen and reduces the NO.sub.2 all in
one step to provide the desired 9-amino-6-demethyl-6-deoxytetracycline
mineral acid salt, 4.
DESCRIPTION OF PREFERRED EMBODIMENTS
##STR1##
Referring to Scheme I, 6-demethyl-6-deoxytetracycline, 1, obtained by
literature procedures previously cited, is treated with a halogenating
agent such as bromine, N-bromosuccinimide, N-chlorosuccinimide, iodine
monochloride or benzyltrimethylammonium dichloroiodate (prepared by the
method of Shoji Kajigaeshi et al., Chem Lett, 2109-14 2112(1987)), in a
solvent such as a concentrated mineral acid. The reaction is carried out
at a temperature between 0.degree. C. and 20.degree. C. until the reaction
is complete. The reaction mixture is added dropwise to cold diethyl ether
and collected. The crude product is recrystallized to eliminate any
7,9-dihalogen-6-demethyl-6-deoxytetracycline formed and gives pure
7-halogen-6-demethyl-6-deoxytetracycline mineral acid salt, 2.
The pure 7-halogen-6-demethyl-6-deoxytetraccycline mineral acid salt, 2,
dissolved in a cold concentrated mineral acid such as concentrated
sulfuric acid, is treated at temperatures ranging from about -15.degree.
C. to +15.degree. C. with a slight molar excess of a nitrating reagent
such as a "mixed acid" or a metal nitrate salt, for from 1-2 hours. The
reaction is added dropwise to cold diethyl ether and collected to give
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt, 3.
Preferably, 6-demethyl-6-deoxytetracycline, is converted directly to
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt, 3, in
one step. 6-Demethyl-6-deoxytetracycline, 1, is dissolved in a cold
solvent such as a concentrated mineral acid, and treated with a
halogenating agent such as bromine, N-bromosuccinimide,
N-chlorosuccinimide or benzyltrimethylammonium dichloroiodate (prepared by
the method of Shoji Kajigaeshi et al.). The reaction is stirred for 45
minutes at a temperature between 0.degree. C. and 20.degree. C. A slight
molar excess of a solid metal nitrate salt or a "mixed acid" is added and
the stirring is continued at between -15.degree. C. and +15.degree. C. for
an additional 30 minutes to 2 hours. The reaction is added dropwide to
cold diethyl ether. The resulting solid is collected, triturated with an
alcohol, filtered and the filtrate is added to diethyl ether. The yellow
solid is collected to give pure
7-halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt, 3, in
93% yield
7-Halogen-9-nitro-6-demethyl-6-deoxytetracycline mineral acid salt, 3,
dissolved in a solvent mixture such as 2-methoxyethanol, methanol or
ethanol with IN sulfuric acid or lN hydrochloric acid, is catalytically
reduced with 10-30% by weight of a Group VIII metal catalysts, their salts
or rare metal oxides at room temperature under an atmosphere of from 1-40
psi of hydrogen. The reaction is filtered, added slowly to isopropanol and
collected to give pure 9-amino-6-demethyl-6-deoxytetracycline mineral acid
salt, 4.
This invention will be described in greater detail in conjunction with the
following examples.
EXAMPLE 1
[4S-(4alpha, 12a
alpha)]-7-Bromo-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,1
2a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide sulfate
A solution of 4.14. g of 6-demethyl-6-deoxytetracycline, prepared by the
described literature procedure, and 1.99 g of N-bromosuccinimide dissolved
in 50 ml of concentrated sulfuric acid is stirred at 0.degree. C. for 45
minutes or until solution occurs. The reaction mixture is added dropwise
to 2 L of cold diethyl ether. The resulting precipitate is collected and
dried. The solid is dissolved in 2-methoxyethanol, triturated with
methanol, collected, washed with methanol and diethyl ether and dried to
give 6.22 g of crude product. The solid is recrystallized from
2-methoxyethanol and methanol to give 3.1 g of pure product. MS(FAB): m/z
493 (M+H). .sup.1 H NMR(CD.sub.3 SOCD.sub.3): .delta. 4.3(s, lH, 4-H),
6.8(d, lH, 9-H) and 7.75(d, IH, 8-H).
EXAMPLE 2
[4S-(4alpha,
12aalpha)]-7-Bromo-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,1
2,12a-tetra-hydroxy-9-nitro-1,11-dioxo-2-naphthacenecarboxamide sulfate
To one and one tenth grams of product from Example 1, dissolved in 10 ml of
cold concentrated sulfuric acid, is added 1.2 ml of 10% nitric acid in
concentrated sulfuric acid. The reaction is stirred at 0.degree. C. for
11/2 hours and then added dropwise to 500 ml of ice cold diethyl ether.
The resulting solid is collected, washed 3.times. with diethyl ether and
dried under vacuum to give 1.06 g of the desired product (90%). MS(FAB):
m/z 538 (M+H).
.sup.1 HNMR (CD.sub.3 SOCD.sub.3): .delta. 4.3(s, IH, 4-H) and 8.48 (s, IH,
8-H).
EXAMPLE 3
[4S-(4alpha,
12aalpha)]-7-Bromo-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,1
2,12a-tetra-hydroxy-9-nitro-1,11-dioxo-2-naphthacenecarboxamide sulfate
To a 0.degree. C. solution of 0.414 g of 6-demethyl-6-deoxytetracycline and
10 ml of concentrated sulfuric acid is added 0.196 g of
N-bromosuccinimide. The reaction action is stirred at 0.degree. C. for 45
minutes followed by the addition of 0.11 g of solid potassium nitrate. The
mixture is stirred, at 0.degree. C., for 30 minutes and then poured into
500 ml of cold diethyl ether. The solid is collected, washed with diethyl
ether and dried to give 0.72 g of crude product. The product is purified
by trituration with methyl alcohol and isopropyl alcohol, filtered, and
the filtrate added to cold diethyl ether. The yellow solid is collected to
give 0.59 g of the desired product (93%).
MS(FAB): m/z 538 (M+H).
.sup.1 HNMR (CD.sub.3 SOCD.sub.3): .delta. 4.3(s, lH, 4-H) and 8.48 (s, lH,
8-H).
EXAMPLE 4
[4S-(4alpha)]-9-Amino-4-(dimethylamino)-1,4,4a,5,.5a,6,11,12a-octahydro-3,1
0,12-12-12a-tetra-hydroxy-1,11-dioxo-2-naphhthacenecarboxamide sulfate
A mixture of 1.272 g of product from Example or 2 or 3, dissolved in 50 ml
of 2-methoxyethanol and ml of IN sulfuric acid, and 0.30 g of 10%
palladium-on-carbon is hydrogenated in a Parr apparatus for 1 hour at 40
psi. The reaction is filtered thru a pad of diatomaceous earth and the
filtrate is poured slowly into 500 ml of isopropanol and diethyl ether
(1:4). The yellow solid is collected, washed with diethyl ether and dried
to give 1.02 g of desired product (97%).
MS(FAB): m/z 430 (M+H). .sup.1 HNMR (CD.sub.3 SOCD.sub.3): .delta. 4.3(s,
lH, 4-H), 6.8(d, lH, 7-H) and 7.45(d, lH, 8-H).
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